Febuxostat intermediate and preparation method thereof

A technology for febuxostat and intermediates, which is applied in the field of new febuxostat intermediates and their preparation, can solve the problems of long operation cycle, low product purity, unfavorable production operation and the like, and achieves ideal yield and high purity , and good quality results

Active Publication Date: 2014-05-14
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The key of this type of method is to introduce cyano group after preparing aldehyde group. The method of preparing aldehyde group uses expensive and highly corrosive trifluoroacetic acid, which has high cost, great equipment loss, and is not easy to industrialize.
[0012] In addition, Japanese patent documents JP11060552 and JP1045733 report using polyphosphoric acid as a solvent to introduce aldehyde groups, but polyphosphoric acid will polymerize and become extremely viscous during the reaction process, which is not conducive to production operations, and the product purity is low
[0013] Chinese patent document CN102002017 reports the use of polyphosphoric acid and a variety of strong acids in combination to form a mixed acid as a solvent to prepare aldehyde groups. This method will still use a large amount of strong acid, resulting in greater acid pollution.
[0016] More expensive tetrakistriphenylphosphopalladium will be used to do catalysis in this type of synthetic method, and raw material cost is higher; The yield of preparing boric acid pinacol ester and bicyclic docking these two step reactions is all relatively low, only has 72% and 75%
And all need column purification, resulting in long operation cycle, not suitable for actual production

Method used

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  • Febuxostat intermediate and preparation method thereof
  • Febuxostat intermediate and preparation method thereof
  • Febuxostat intermediate and preparation method thereof

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preparation example Construction

[0090] C. The preparation method of febuxostat

[0091] The present invention also provides a method for preparing Febuxostat, wherein said Febuxostat is shown in formula I:

[0092]

[0093] Described method comprises the following steps:

[0094] Make the compound shown in formula V carry out the hydrolysis reaction shown below in the presence of hydrolysis catalyst, to obtain described Febuxostat:

[0095]

[0096] Preferably, the molar ratio of the hydrolysis catalyst to the compound represented by formula V is (1-10):1; more preferably (1-5):1. If the molar ratio of the hydrolysis catalyst to the compound represented by formula V is too high, the raw material cost will be increased; if it is too low, the hydrolysis reaction will be incomplete.

[0097] Preferably, the hydrolysis catalyst is an alkali; preferably, the alkali is selected from sodium hydroxide or potassium hydroxide.

[0098] Preferably, the reaction temperature of the hydrolysis reaction is 50°C to...

Embodiment 1

[0124] Embodiment 1: the preparation of the Grignard reagent shown in formula III:

[0125] Keep warm at about 30°C, pass nitrogen protection, add 200ml tetrahydrofuran (hereinafter referred to as THF), 72.9g (3.00mol) of pretreated magnesium chips, and 12.7g (0.05mol) of iodine into a 1000ml reaction bottle, and stir for 1 After 1 hour, the temperature was raised to 45°C, and at the same time, a mixture of 680.4g (2.50mol) of 5-bromo-2-isobutoxybenzamide and 12.7g (0.05mol) of iodine dissolved in 250ml THF was slowly added dropwise. React at 45°C for 5 hours, cool to 15°C to 20°C, and set aside.

[0126] Among them, the pretreatment method of magnesium chips is as follows: stir and wash with 5% hydrochloric acid for 30 minutes, quickly filter and rinse with acetone (minimize the time of contact with air), and use it immediately after vacuum drying.

Embodiment 2

[0127] Embodiment 2: the preparation of the Grignard reagent shown in formula III:

[0128] Keep warm at about 20°C, pass nitrogen protection, add 200ml methyl tert-butyl ether, 72.9g (3.00mol) of pretreated magnesium chips, and 12.7g (0.05mol) of iodine into a 1000ml reaction bottle, and stir for 1 hour , the temperature was raised to 50°C, and at the same time, a mixture of 680.4 g (2.50 mol) of 5-bromo-2-isobutoxybenzamide dissolved in 300 ml of methyl tert-butyl ether and 12.7 g (0.05 mol) of iodine was slowly added dropwise, After dropping, keep warm at 45°C and react for 6 hours, cool to 15°C to 20°C, and set aside.

[0129] Among them, the pretreatment method of magnesium chips is as follows: stir and wash with 5% hydrochloric acid for 30 minutes, quickly filter and rinse with acetone (minimize the time of contact with air), and use it immediately after vacuum drying.

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Abstract

The invention provides a febuxostat intermediate and a preparation method thereof. The febuxostat intermediate is a chemical compound shown as the formula IV. The formula IV is described in the specification. The yield of febuxostat prepared by a method of preparing the febuxostat from the febuxostat intermediate and by the preparation method of the febuxostat intermediate is high and can be higher than 90%. The impurity of the febuxostat is high and can be higher than 99%. In addition, the preparation method of the febuxostat intermediate and the method of preparing the febuxostat from the febuxostat intermediate are free of highly toxic cyanide. A dehydrating agent used in the method is economic and environmental-friendly and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of medicines, and in particular relates to a novel febuxostat intermediate and a preparation method thereof. Background technique [0002] Gout is hyperuricemia caused by excessive uric acid produced in the body. It has always been one of the important causes of disabling paralysis, and its incidence has been showing an upward trend in recent years. The production of uric acid is a very complicated process, which requires the participation of some enzymes, among which xanthine oxidase is a major enzyme that promotes uric acid synthesis. [0003] Febuxostat is an inhibitor that selectively inhibits the activity of xanthine oxidase, and can effectively reduce the level of uric acid in patients with gout. Its English name is: Febuxostat, and its chemical structure is as shown in formula I. 2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, CAS number: 144060-53-7. [0004] [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 王威徐虹张铮任娟
Owner NEW FOUNDER HLDG DEV LLC
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